DESCRIPTION Abstract: A central tenet of biology is the accurate flow of information from nucleic acids to proteins through the genetic code. It is commonly believed that translation deviating from the genetic code is to be avoided at all times in cells. By using a new genomic method, we have discovered that in contrary, mammalian cells can deliberately reprogram the genetic code with the amino acid methionine upon innate immune activation and chemically triggered oxidative stress. Reprogramming the genetic code occurs through aminoacylation of non-methionyl-tRNAs with methionine, and is inducible upon regulated production of the reactive oxygen species (ROS) in the cell. We propose that mis-translation via regulated tRNA misacylation is a common mechanism for stress response for cells. We will explore and test hypotheses on biological effects and function on tRNA misacylation with methionine and establish a full spectrum of tRNA misacylation for all amino acids and their participations in translation in mammalian cells. The results and conceptual understanding obtained here shall help establish a new field of biology of mis-translation. Public Health Relevance: We have discovered that mammalian cells deliberately reprogram the genetic code with the amino acid methionine upon innate immune activation and oxidative stress. Here we aim to establish biology of mis-translation via tRNA misacylation as a new mechanism of stress response in mammalian cells. THE FOLLOWING RESUME SECTIONS WERE PREPARED BY THE SCIENTIFIC REVIEW OFFICER TO SUMMARIZE THE OUTCOME OF DISCUSSIONS OF THE REVIEW COMMITTEE ON THE FOLLOWING ISSUES. COMMITTEE BUDGET RECOMMENDATIONS: The budget was recommended as requested. SCIENTIFIC REVIEW OFFICERS NOTES: Since the NIH Director's Pioneer Award applications are reviewed differently from other NIH grant mechanisms, criterion scores and percentiles are not assigned. Please ignore the Administrative Budget Note on page one and the Notice below regarding re